Single gene variant is what keeps small dogs small

What’s the difference between a tiny Chihuahua and an enormous Great Dane? When it comes to their size, the answer begins with a single gene. A gene hunt involving thousands of dogs reveals that small dogs all share a line in their DNA code that says “be tiny.” The more than 400 dog breeds all stem from a gray wolf ancestor some 15,000 years ago. Since then, humans have bred their canine companions to accentuate various traits and shapes. Consequently, modern dogs show the greatest range of size of any single mammal species. Nathan Sutter, a geneticist at the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland, wanted to know what genes were involved in making this great diversity possible. Working with NHGRI geneticist Elaine Ostrander, Sutter and his colleagues first studied 463 Portuguese Water dogs, which range from 11 to 34 kilograms. The dogs were all related, and based on their family history and pattern of size variation, the researchers focused on a 15-million-base region of chromosome 15. (Dogs have 39 pairs of chromosomes.)

To pin down the exact gene, Sutter sequenced this DNA from four large and four small Portuguese water dogs and nine dogs that weighed less than 9 kilograms or more than 30 kilograms. The researchers found 302 places where the base varied from one individual to the next–called a SNP for single nucleotide polymorphism. By looking at those SNPs in the original 463 dogs, they determined a gene for the growth-promoting protein IGF1 was likely responsible for 15% of the size differences in these animals. Finally, they determined how the IGF1 gene differed between big and little Portuguese water dogs and between 526 dogs from 23 small and 20 giant breeds. They detected particular patterns of SNPs in each size class. A further genetic analysis of 3241 dogs from 143 breeds pinpointed one SNP, in the middle of the IGF1 gene, that corresponded with smaller size, Sutter and his colleagues report this week in Science.

The variant appears in so many small breeds, many dating back centuries, that it must have arisen early in the history of dogs, the authors argue. It may have become widespread because humans tended to select for more compact animals that were easier to feed, house, and transport, says co-author Robert Wayne from the University of California, Los Angeles. Just how this IGF1 variant controls size remains unclear. “This is a fascinating revelation, [that] such a complex phenomenon as determining an organism’s size is apparently masterminded by this one gene,” comments Carolyn Bondy, an endocrinologist at the National Institute of Child Health and Human Development, Bethesda, Maryland. John W. Fondon III, a biochemist at the University of Texas Southwestern Medical Center in Dallas, says, “This will become the textbook example” of how the unparalleled diversity of dogs can teach us about the genetics of complex traits in mammals.